UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study.

Lamotrigine (LTG) is metabolized by UGT1A4 but UGT2B7 also contributes to its glucuronidation. The aim of this study was to determine whether UGT2B7_- 161C>T and UGT2B7_372A>G polymorphisms contribute to the intersubject variability in LTG concentration-to-dose ratio (LTG-CDR) in epileptic patients. Fifty-three white epileptic patients attending the Neuropediatric and Neurology Services at the Marqués de Valdecilla University Hospital, in whom LTG serum concentration was to be measured for pharmacokinetic monitoring, were selected according to predefined criteria for LTG-CDR evaluation. All patients had at least one steady-state LTG serum concentration obtained before the first dose in the morning. Patients were classified in 3 groups of comedication: (1) LTG in combination with metabolism-inducer anticonvulsants (n = 22), (2) LTG in combination with valproate (n = 13), and (3) LTG as monotherapy (n = 16) or in combination with valproate and inducers (n = 2). Genotypes were determined by Applied Biosystems Genotyping Assays with TaqMan probes. A significant association was found between LTG-CDR and UGT2B7_-161C>T polymorphism (P = 0.021) when patient age and concomitant antiepileptic drugs were taken into account. Comedication explained 70% of the LTG-CDR variability, patient age 24%, and UGT2B7_-161C>T 12%. In contrast, a significant association between LTG-CDR and this polymorphism was not found in the bivariate study when age and comedication groups were not considered. A significant association between UGT2B7_372A>G and LTG-CDR was not found in the bivariate or the multivariate studies. UGT2B7_-161C>T polymorphism is significantly associated with LTG-CDR when comedication with other antiepileptic drugs and patient age are taken into account in a multivariate analysis.

Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy.

Epilepsy drug-resistance may depend on the metabolism of antiepileptic drugs (AEDs), transport to the epileptic focus and/or target sensitivity. Furthermore, drug response depends on multiple characteristics of the patient, the epilepsy, and the antiepileptic drugs used. We have investigated the association between polymorphisms related to antiepileptic drug metabolism (CYP2C9, CYP2C19, and UGT), transport (ABCB1), and targets (SCN1A) both in a crude analysis and after adjusting by clinical factors associated with drug-resistance, and stratifying by patient age or aetiology of epilepsy. Caucasian outpatients (N=289), children (N=80) and adolescent-adults (N=209), with idiopathic (N=69), cryptogenic (N=97) or symptomatic epilepsies (N=123) were selected when they had either drug-resistance (with at least four seizures over the previous year after treatment with more than three appropriate AEDs at appropriate doses) or drug responsiveness (without seizures for at least a year). Samples were genotyped by allelic discrimination using TaqMan probes. No significant association between polymorphisms and drug-resistance was found either in the crude analysis or in the adjusted analysis. However, adults with the ABCB1_3435TT or 2677TT genotypes had a lower risk of drug-resistance than those with the CC or the GG genotypes. Furthermore, patients with symptomatic epilepsies with the ABCB1_3435CT or TT genotypes had a lower risk of drug-resistance than those with the CC genotype. An opposite but insignificant tendency was found in children and in idiopathic epilepsies. Although replication studies will be needed to confirm our results, they suggest that stratification by patient age and by the aetiology of epilepsy could contribute to unmask the association between ABCB1 polymorphisms and drug-resistance of epilepsy.

Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics.

OBJECTIVE: It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy. METHODS: The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22). The study duration was 16 months (four phases of 4 months each). VPA pharmacokinetics data were also compared in the different regimens. Mean VPA dosage was of approximately 870 mg/day (approximately 22 mg/kg/day) and mean VPA concentration was of approximately 89 mg/l at 12 h post-dose and of 54 mg/l at 24 h post-dose. RESULTS: By intention in treatment there were no significant differences in efficacy (73%, 83%, 77% and 75%, respectively) or in adverse reaction frequency (56%, 58%, 67% and 46%, respectively). There were significant differences, however, in patient (or parents) preference, the order being ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%). The mean VPA serum concentration fluctuation between 4 h and 0 h post-morning-dose was nonsignificantly lower after CVbid than after ChVbid. Fluctuation was significantly higher after ChVom than after CVbid or ChVbid. The mean VPA serum concentration difference between 12 h and 24 h post-dose was approximately 40 mg/l. CONCLUSION: Although our results should be confirmed by a larger study, they suggest that the efficacy and tolerability of chrono valproate is similar to that of conventional valproate, and that the main advantage is the once-daily administration.

10-Hydroxycarbazepine serum concentration-to-oxcarbazepine dose ratio: influence of age and concomitant antiepileptic drugs.

This study was done to evaluate the association between patient age and the concomitant use of enzyme-inducing antiepileptic drugs (AEDs) and oxcarbazepine (OXC) concentration-to-dose ratio (CDR) by a multivariate analysis. The influence of patient age and concomitant AEDs on the trough steady-state serum concentration of 10-hydroxycarbazepine (OHC) normalized to 1 mg/kg body weight of OXC or concentration-to-dose ratio (OHC-OXC-CDR) was assessed by analysis of covariance. Samples were collected from 106 patients (90% outpatients), aged 1-80, who were receiving OXC either alone (n = 41) or in combination with other AEDs (n = 65). The average OHC-OXC CDR was 0.70 +/- 0.26 (mean +/- SD). Analysis of covariance showed that patient age was influential (P < 0.001) and that there was a difference between the noninducers group (OXC or OXC + lamotrigine, topiramate, or valproate) and the inducers group (OXC + phenobarbital or phenytoin) (P < 0.001). The OHC-OXC CDR increased with age (r = 0.14, P < 0.001) and was approximately 48% lower in children aged 6 or less than in patients over 45, and approximately 32% lower in the inducers group than in patients receiving OXC alone. The correlation between OHC-OXC CDR and the age of the patients concerned with OXC alone was r = 0.48, P < 0.001. In the noninducers group the OHC-OXC CDR was 0.59 +/- 0.24 in patients aged 11 or less (n = 16), and 0.81 +/- 0.23 in patients over 11 years (n = 62). In the inducers group it was 0.25 +/- 0.11 in patients aged 11 or less (n = 3) and 0.57 +/- 0.18 in patients over the age of 11 (n = 25). The OHC-OXC CDR increased with patient age and decreased in the presence of enzyme-inducing AEDs in epileptic patients chronically treated with OXC. These influences may be clinically relevant, and, therefore, patient age and the presence of inducers should be considered in estimating either compliance or the OXC dose needed to achieve a desired OHC concentration.

Association between patient age and gabapentin serum concentration-to-dose ratio: a preliminary multivariate analysis.

OBJECTIVES: To evaluate the association between patient age and gabapentin (GBP) concentration-to-dose ratio by a multivariate analysis. METHODS: The association between patient age and the trough steady-state serum concentration of gabapentin (GBP) normalized to 1 mg/kg body weight or concentration-to-dose ratio (CDR) was retrospectively assessed by analysis of covariance. Potential confounding factors considered were GBP dosage, the number of GBP doses per day, and the presence of concomitant antiepileptic drugs (AEDs). Concentrations that had been measured in predose "trough" samples collected from 66 patients, aged 5-84 years, with partial seizures or neuropathic pain chronically receiving GBP BID (n = 21) or TID (n = 45), alone (n = 15) or in combination with other AEDs (n = 51) were used in this retrospective analysis. RESULTS: Average GBP CDR was 0.23 +/- 0.18 (mean +/- SD). The GBP CDR increased with age (r2 = 0.46, P < 0.001), and the correlation was improved when only samples from patients taking GBP BID were separately considered (r2 = 0.68, P < 0.001). The ratio was lower in the 10 children younger than 11 years of age (0.07 +/- 0.05) than in 8 adolescents aged 12 to 18 years (0.14 +/- 0.04), lower than in 35 adults aged 19 to 65 years (0.22 +/- 0.13), and lower than in 13 patients older than 65 years of age (0.45 +/- 0.20) by 1-way analysis of variance (F = 19.4, P < 0.001). Analysis of covariance showed a significant influence on GBP CDR of patient age (P < 0.001) and the number of GBP daily doses (P < 0.01), but GBP daily dosage or concomitant AEDs had no significant influence on the ratio. CONCLUSIONS: In this retrospective study of a small, select group of patients, (1) the GBP CDR increased significantly with age when potential confounding factors such as GBP dosage, number of GBP doses per day, and concomitant AEDs were considered by analysis of covariance, and (2) patients older than 65 years, even without any known renal disease, may have double GBP CDR than younger adults and, therefore, may need half of the GBP dose per body weight to achieve a similar concentration.

Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and monitoring implications.

The influence of age and concomitant antiepileptic drugs (AEDs) on the trough steady-state serum concentration of topiramate, normalized to 1 mg/kg body weight or concentration-to-dose ratio (TPM-CDR), was assessed using multivariate methods in samples from 94 epileptic patients (38 under 11 years and 56 over 11 years of age), most of whom were outpatients receiving either just TPM (n = 20) or TPM in combination with other AEDs (n = 74). Analysis of the covariance showed that the age of the patients was influential (P < 0.001) and also showed a difference in TPM-CDR between the non-inducers group (TPM or TPM + lamotrigine or valproate) and the inducers group (TPM + carbamazepine, phenobarbital, or phenytoin) (P < 0.001). The TPM-CDR was 0.4 +/- 0.1 in patients under 11 years with inducers (n = 7), 0.8 +/- 0.3 in patients over 11 years with inducers (n = 32), 1.1 +/- 0.4 in patients under 11 years with noninducers (n = 30), and 1.8 +/- 0.6 in patients over 11 years with noninducers (n = 21). A two-way analysis of the variance showed differences between patients under 11 years and those over 11 years (P < 0.001), and between the noninducers and inducers groups (P < 0.001). TPM-CDR was nearly 50% lower in patients under 11 years than in patients over 11 years, and in patients with TPM + inducers than in patients with TPM or TPM + noninducers, in both children and adults. To achieve the same serum concentration of TPM, children will need double the daily dose per kilogram of TPM required by adults, and both children and adults taking enzyme-inducing AEDs will require double the dose needed by those who do not take them.